We propose to discover and characterize antagonists of the association of beta-catenin with TCF/LEF-1 (T-cell factor/lymphoid enhancer factor-1), a crucial step in WNT signaling pathway. Deregulation of beta-catenin signaling was implicated in a number of malignancies, which makes beta-catenin/TCF interaction a promising target for prevention and treatment of a variety of tumors, such as breast, prostate, and colon cancer as well as leukemia. The structure of the beta-catenin armadillo repeat domain was solved, alone and in complex with TCF. Our powerful proprietary high throughput docking technology allows us to rapidly discover novel small-molecule ligands using the receptor structure. Only a relatively small number of compounds will need experimental testing to confirm activity. Initial hits found in Phase I of the project will be thoroughly characterized for their therapeutic value and further optimized in Phase II into leads with high potential for commercial applications. Our expertise in the structure-based ligand discovery and design, the synergistic efforts of experts in structural biology at Molsoft and cancer biology at The Burnham Institute, access to large collections of screening compounds, and the lead discovery engine developed by Molsoft using its ICM biocomputing platform, will all be critical for the success of our undertaking.